A new study published in Nature Communications identified two new functions of a regulatory protein called synaptotagmin-17, findings that have the potential to inform better treatments for spinal injuries and neurodegenerative disease.
There are 17 different varieties of the protein synaptotagmin (syt), most of them localized in the brain’s hippocampus. Just a few of syt’s isoforms have previously been investigated, and these varieties usually regulate exocytosis, the process by which molecules exit a cell through the cell membrane.
Ewa Bomba-Warczak, PhD, then a graduate student at UW-Madison and now a postdoctoral fellow in the Savas laboratory and co-author of the study, noticed that over-expression of syt-17 in neurons caused axons to grow. Seeking to learn more about the syt-17, one isoform of the protein, scientists caused the protein to be over-expressed and tagged it with a fluorescent compound, so it would visible in neurons. Soon after that, they discovered two distinct populations, still in the hippocampus, but seemingly uninvolved in exocytosis.
The first population clustered near the Golgi complex of hippocampal neurons. The Golgi complex is a cellular organelle that packages and ships molecules, receiving them from the endoplasmic reticulum and wrapping them in transport vesicles them before sending them on their way to other locations, both inside and outside the cell.
The scientists discovered that syt-17 helps the Golgi complex receive vesicles that are later shipped to the outer extremities of the neuron, aiding axon regrowth after injury. When syt-17 was deleted, this outgrowth was impaired, and when syt-17 was overexpressed, axon regrowth was improved.
Mature neurons have a limited capacity for axon regrowth, so when these axons are severed they usually fail to regenerate. As boosting syt-17 produced no other changes in nerve structure, this strategy could have future clinical value for treating spinal or nerve injuries, according to the authors, allowing mature nerve cells to more readily regenerate.
“It would be very exciting to see whether syt-17 can in fact aid in axon regrowth after injury, such as spinal cord injury or in neurodegeneration,” Bomba-Warczak said.
The other population of syt-17 was found in the early endosome, a “sorting station” that determines where molecules go after entering a cell. In this population, deleting the protein isoform led to a disruption of sorting and accumulation of excess neuroreceptors, which overloaded the neuron with chemical signals and caused defective synapse activity. According to the authors, this dysregulation resembles that observed in long-term depression (LTD), a chronic reduction in synapse effectiveness that occurs in some neurodegenerative diseases, but also by itself.
Patients with disorders characterized by LTD often have memory deficits linked to poor hippocampal activity, and a lack of syt-17 could be one factor, noted the study authors.
“This pool of syt-17 is key for synapse firing, and could be studied as a potential regulator of synapse plasticity, and potentially even in seizure research,” Bomba-Warczak said.
In the future, further study of syt-17’s mechanisms could produce clinical impacts, the authors said, and investigating little-known isoforms of proteins represents an untapped well of therapeutic or scientific advances.
Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Neuro-Oncology, and an assistant professor of Medicine and of Pharmacology, was also a co-author of the study.
This study was supported by National Institutes of Health grants MH061876 and R35NS097362.
